1) Field of the Invention
The present invention relates to water soluble salts of biotin and to the relative therapeutical compositions, which can be administered by oral, parenteral and topical route, particularly suitable for the treatment of vitamin H deficiency, with dermatological manifestation, for the treatment of the deficiency in multiple carboxylase enzymes in the different phases of childhood, for the treatment of dermatologic pathologies, like the seborrheal dermatitis of the newborn, and for the treatment of diabetes and its complicating diseases.
2) The State of the Art
The clinical role of biotin, better known as vitamin H and characterized by the following formula: ##STR1## was ascertained in 1942 by Sidenstricker and co-workers, who demostrated that the socalled "egg-white injury" can be defeated administering biotin.
The experimental work hereinabove aimed to show which were the effects of a vitamin H deficiency in human beings. In fact the patients undergoing such a treatment were only fed with egg-white, wherein biotin combines with a protein, the avidin, which prevents its bioavailability, thus causing a state of deficiency. This experimental work and the successive ones clearly proved that such vitamin deficiency in human beings leads to the formation of a non-pruriginous dermatitis and then to maculosquamosal dermatitis, change of the mental state, myalgia, hyperesthesis, localized paresthesis, anorexia, coronary ischemia.
All these secondary effects disappeared and the patients came back to normality following administration of biotin for a certain time. Moreover, in the last 20 years the interest was aroused in the application of the therapeutical use of molecules effective as cofactors in several enzymatic reactions. It was thus proved that biotin can be a therapeutical cofactor like pyridoxine or vitamin D. It was for instance proved that although biotin is uneffective in treating diseases caused by single carboxylase enzymes insufficiency, like the insufficiency in propionyl-Co A carboxylase (being the cause of ketonic hyperglycinemia), the insufficiency in pyruvate-carboxylase (being the cause of lactic acidosis, persistent in the different phases of childhood), and the insufficiency in .beta.-methyl-crotonylcarboxylase (which can also cause juvenile spinal muscular atrophy, or, always during the childhood, a serious acidosis bound to metabolic disorders), the same biotin proved on the contrary to be effective in diseases coming from a deficiency in multiple carboxylase enzymes, whose symptoms are mostly common to those of the pathologies hereinabove, and provoked by deficiencies in single carboxylase enzymes (K. S. ROTH "Biotin in clinical medicine--a review "The American Journal of clinical nutrition" 34: September 1981, pp. 1967-1974).
Vitamin H also proved to be particularly effective in the treatment of the seborrheal dermatitis in the newborn, whose origin was not yet ascertained; probably such dermatitis seems to be abscribed to the low amount of vitamin H in the breast milk and possibly to poor digestion or persistent diarrhoeia (Khrishnamurti-Dachshinamurti and Jasbir Chauan-Biotin-Vitamins and Hormones, vol 45-1989 PP 337-385).
Biotin moreover can advantageously be utilized in the therapy of diabetes and its complicating diseases.
It has recently been proved through pharmacological tests on mice as well as through clinical tests on human beings that said active principle not only lowers the blood glucose level in insulin-dependent diabetics, but can also reduce the post-prandial glucose level, increase glucose tolerance and lower resistance to insulin also in insulin-independent diabetes (Alluru Reddi, Barbara De Angelis, Oscar Frank, Norman Lasker and Herman Baker "Biotin supplementation improves glucose and insulin tolerances in genetically diabetic KK mice" Life Science, Vol. 42, pp 1323-1330; Coggeshall, J. C. et al Ann N.Y. Acad. Science 447-1985 pp. 389-392). Furthermore, it has also recently been proved that such active principle can be advantageously utilized in human beings for the treatment and the prevention of a typical diabetes complicating disease, namely peripheral neuropathies having diabetic origin (D. Koutsikos, B. Agroyannis, H. Tsanakos-Exarchou "Biotin for diabetic peripheral neuropathy; Biomed & Pharmacother (1990) 44, 511-514). Recent studies have shown that biotin is able to activate the enzyme glucokinase as well as insulin.
It is known in fact that the enzyme glucokinase controls the haematic glucose, namely glycaemia, by contemporaneously controlling the utilization and the storage of hepatic glucose, in the form of glycogen, and it is believed that in the pancreas islets the glucokinase acts as a sensor for the glucose controlling the insulin production (J. Chauan, K. Dackshinamurti, J. Biol. Chem:, 266, 1991; pages 10035-38).
Notwithstanding such remarkable therapeutical potential, the uses of biotin are drastically limited because of its poor water solubility. In order to overcome these drawbacks, biotin is employed, according to EP 036902, in the presence of cyclodextrins and of low amounts of a 28% ammonia (solution). These compositions, before being used, are in any case spray dried.
U.S. Pat. No. 4,277,488 describes compositions similar to those of the preceding patent the sole difference residing in that lactose is used instead of cyclodextrin.
Both the compositions above in any case encopass an oral administration of vitamin H.
U.S. Pat. No. 4,725,427 describes water soluble effervescent compositions of vitamins and among them of biotin. In this case the solubility of such active principle is enhanced either by the presence of lactose of by the presence of metals like Ca, Mg, Cu, Zn, Fe and/of Mn, in the form of an amino acid chelate.
According to this patent, therefore, it is still necessary, in order to reach a greater solubilization of biotin, the presence of lactose, coupled with particular metallorganic derivatives. Moreover also in this patent, like, on the other hand, in the other papers hereinabove, the sole administration route encompassed for biotin, is the oral one.
Because of the impossibility to obtain in a simple way the solubilization of biotin without using said complicated methods, the biotin administration by a route different from the oral one was never taken into serious consideration.
Only according to JP Pat. Appln. 2096581 as summarized in Derwent Data Bank biotin previously converted into an ester is topically administered on the skin or on hair utilizing as the vehicle a gel or creamy suspension of water and of an organic solvent.
These biotin esters, partially soluble either in the organic solvent of in water, proved to be particularly fit for this goal.
The need was felt for biotin derivatives allowing the use of such active principle not only by oral route but also by parenteral and in particular by intramuscular or intravenous route.